Abstract: SA-PO294

Galectin-1 Is a New Renal Fibrosis Gene Upregulated in Type I and Type II Diabetes

Session Information

Category: Cell Biology

  • 204 Extracellular Matrix Biology, Fibrosis, Cell Adhesion

Author

  • Habib, Samy L., UTHSCSA, San Antonio, Texas, United States
Background

Chronic exposure of tubular renal cells to elevated blood glucose contributes to tubulointerstitial changes seen in diabetic nephropathy. Tubular cells are primary targets of hyperglycemia, and chronic exposure to elevated blood glucose levels contributes to the tubulointerstitial changes seen in overt diabetic nephropathy.

Methods

Kidney tissues from wild type and diabetic mice from both type 1 DM (Akita) and type 2 (db/db) groups at age of 4, 6, 8 months old were used. RNA sequence and analysis of Gal-mRNA were performed in RNA extracted from kidney tissues. Proximal tubular epithelial renal cells treated with high glucose and/or HG+Insulin for different time points were used to measure promoter activity and protein expression of Gal-1. Gal-1 was cloned and transcription factor AP4 was i immunoprecipitated to identify the binding of Ap4 to Gal-1 promoter. siRNA of Gal-1, AP4 and tuberin as well as Gal-1 inhibitor and Akt inhibitor were used to test the effect of its downregulation on Gal-1 expression and promoter activity.

Results

In the present study, we identified a new fibrosis gene called Galectin-1 (Gal-1) that highly expressed in tubular cells in kidney of type I and type II mouse models of diabetes. Gal-1 protein and RNA expression showed significant Increased in kidney cortex of Akita and db/db mice compared to wild type mice. Mouse proximal tubular exposed to high glucose (HG) and HG+Insulin showed significant increase in phosphorylation of Akt that associated with significant increase in expression of Gal-1. We identified that AP4 binds to Gal-1 promoter to upregulates its function. The mutated binding sites of Ap4 to Gal-1 promoter showed decease in protein and function activity of Gal-1. Inhibition of Gal-1 by OTX-008 showed significant decrease in phosphorylation of Akt and expression of AP4 and Gal-1 protein/promoter activity. In addition, downregulation of Ap4 by siRNA resulted in significant decrease in protein expression and promoter activity of Gal-1.

Conclusion

In summery, our data showed that Gal-1 is highly expressed in kidney of type 1 and II diabetic mouse and Ap4 is a major transcription factor that activates Gal-1 under hyperglycemia through activation of Akt. Inhibition of Gal-1 by OTX-008 blocks activation of Akt and prevent accumulation of Gal-1 suggest a novel role of Gal-1 inhibitor as possible therapeutic target to treat renal fibrosis in diabetes.

Funding

  • Veterans Affairs Support